P35. Fibroblast growth factor signals and their connection to micrornas in malignant pleural mesothelioma
CELCC 2014 Abstracts

P35. Fibroblast growth factor signals and their connection to micrornas in malignant pleural mesothelioma

Karin Schelch1,2,3, Michaela Kirschner3, Christina Wagner1, Mir Alireza Hoda1,2, Walter Klepetko2, Balazs Dome2, Balazs Hegedus2, Walter Berger1, Glen Reid3, Michael Grusch1

1Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria; 2Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria; 3Asbestos Diseases Research Institute, University of Sydney, Australia, Sydney, Australia

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy characterized by increasing incidence, poor outcome and limited therapeutic options due to frequent resistance to chemo- and radiotherapy. MicroRNAs (miRNAs) are highly conserved RNAs which control gene expression via translational repression of mRNA. Previous data show that the miR-15/16 family has tumor suppressor function and is downregulated in MPM. Fibroblast Growth Factors (FGFs) and their Receptors (FGFRs) are upregulated in MPM. Their signals are important players in MPM malignant behavior and inhibition leads to reduced growth in vitro and in vivo. Several FGFs/FGFRs are predicted mir-15/16 targets. Aim of this study was to investigate the interaction of the miR-15/16 family and FGF signals in MPM.

Methods: Target gene and miRNA expression was determined by TaqMan-based RT-qPCR and western blot. Mimics were used to restore miRNA expression and recombinant FGF2 or the FGFR1-specific inhibitor PD166866 (PD) to stimulate or inhibit FGF-mediated downstream signals. Effects on cell growth were assessed via SYBR green staining and colony formation assays.

Results: Expression analysis confirmed the loss of miR-15/16 in all cell lines tested and showed a consistent downregulation of target genes after transfection with miRNA mimics. Restoration of mir-15/16 led to dose-dependent growth inhibition and reduced colony formation. Cells which are more sensitive to FGFR inhibition exhibited a more pronounced response. FGF2 could reduce these effects, but only when added shortly (24 h) after transfection. Re-expression of miR-15/16 resulted in slightly decreased PD efficacy, indicating target competition. Taqman low density array screens showed several miRNAs changed after stimulation/inhibition of FGF signals.

Conclusions: These data suggest that miR-15/16 achieves a tumor-suppressor function due to translational repression of FGF signaling. Restoration of this miRNA family represses MPM cell growth especially in MPM cells sensitive to the FGFR1 inhibitor PD166866 and therefore could go in line with inhibition of FGF signals in novel therapeutic approaches.

Keywords: Mesothelioma; fibroblast; micro-RNA

doi: 10.3978/j.issn.2218-6751.2014.AB047

Cite this article as: Schelch K, Kirschner M, Wagner C, Hoda MA, Klepetko W, Dome B, Hegedus B, Berger W, Reid G, Grusch M. Fibroblast growth factor signals and their connection to micrornas in malignant pleural mesothelioma. Transl Lung Cancer Res 2014;3(5):AB047. doi: 10.3978/j.issn.2218-6751.2014.AB047

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